Abstract
Several factors are thought to be implicated in the occurrence of idiosyncratic adverse drug reactions. The present work aimed to question as to whether inflammation is a determinant factor in hepatic lesions induced by chlorpromazine (CPZ) using the human HepaRG cell line. An inflammation state was induced by a 24-hour exposure to proinflammatory cytokines interleukin-6 (IL-6) and IL-1β; then the cells were simultaneously treated with CPZ and/or cytokine for 24 hours or daily for 5 days. The inflammatory response was assessed by induction of C-reactive protein and IL-8 transcripts and proteins as well as inhibition of CPZ metabolism and down-regulation of cytochrome 3A4 (CYP3A4) and CYP1A2 transcripts, two major cytochrome P450 (P450) enzymes involved in its metabolism. Most effects of cotreatments with cytokines and CPZ were amplified or only observed after five daily treatments; they mainly included increased cytotoxicity and overexpression of oxidative stress-related genes, decreased Na+-taurocholate cotransporting polypeptide mRNA levels and activity, a key transporter involved in bile acids uptake, and deregulation of several other transporters. However, CPZ-induced inhibition of taurocholic acid efflux and pericanalicular F-actin distribution were not affected. In addition, a time-dependent induction of phospholipidosis was noticed in CPZ-treated cells, without obvious influence of the inflammatory stress. In summary, our results show that an inflammatory state induced by proinflammatory cytokines increased cytotoxicity and enhanced some cholestatic features induced by the idiosyncratic drug CPZ in HepaRG cells. These changes, together with inhibition of P450 activities, could have important consequences if extrapolated to the in vivo situation.
Footnotes
- Received March 14, 2014.
- Accepted July 7, 2014.
↵1 Current affiliation: Université de Lille 2, EA4483, Lille, France.
P.B-E.A. and A.S. contributed equally to this work.
This work was supported by the International Research Servier Group, the French-Lebanon Cèdre program 11 S F47/L2 (2011-2012), and the European Community (Contracts Predict-IV-202222 and MIP-DILI-115336). The MIP-DILI project received support from the Innovative Medicines Initiative Joint Undertaking, with resources composed of financial contributions from the European Union's Seventh Framework Programme (FP7/20072013) and EFPIA companies’ in kind contribution; and the researchers were supported by grants from the Lebanese University and Lebanese National Council for Scientific Research (1015/347), the Philippe Jabre association (941/10), and the Doctorate School vie-agro-santé Rennes (to P.B-E.A.); and the Lebanese Association for Scientific Research (to A.S.).
↵This article has supplemental material available at dmd.aspetjournals.org.
- Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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